The glaucomas are a group of vision impairing diseases characterized by progressive optic nerve damage, retinal ganglion cell death, and visual field loss. Risk factors include age, family history, anterior segment dysgenesis, elevated intraocular pressure, and high myopia. The complex nature and constraints of traditional genetic approaches in humans and mammalian model systems has limited the identification of most genes that impact glaucoma. We have developed methodologies and tools in zebrafish to detect and study glaucoma- associated phenotypes in both embryonic and adult zebrafish. We have also isolated mutants that display glaucoma-associated phenotypes. The bugeye mutation is an example in that mutant fish show elevated intraocular pressure, high myopia/buphthalmia, and progressive ganglion cell loss. In the current study we propose experiments to explore the signaling pathways that underlie the ocular phenotypes of bugeye mutants. In addition, we will explore the cell biological basis of the anterior segment and neuronal pathology. Finally, we will study one potential suppressor mutant that we identified through linkage analysis, while also pursuing the identification of other modifier genes of the bugeye phenotypes. PUBLIC HEALTH RELEVANCE: Glaucoma is a significant health problem within the United States and world in general. Due to the complex nature of the disease, a full understanding of the genetic basis and underlying cellular and molecular mechanisms of disease pathology is lacking. In this proposal we describe studies in zebrafish, a relevant model system with many experimental advantages, to understand the genetic susceptibilities and cellular mechanisms of key phenotypes that are associated with glaucoma and that act as risk factors for the disease.